Process for preparing optically active amines

ABSTRACT

In accordance with a novel process, (R)-amines of the formula ##STR1## in which R 1 , R 2  and n have the meanings given in the description, can be prepared by reacting reating N-acyl-amines of the formula ##STR2##  in which R 1 , R 2 , R 3  and n have the meanings given in the description, 
     with lipases which are suitable for cleaving the (R)-enantiomers of N-acyl-amines of the formula (II), in the presence of water and optionally in the presence of an organic diluent, at a pH of between 3.0 and 10.0 and at temperatures of between 0° C. and 80° C.

The present invention relates to a novel process for preparing(R)-amines by the enzymic hydrolysis of N-acylamine racemates.

It has already become known to prepare optically activeN-p-aminophenyl-acetylamino derivatives by the enzymic cleavage of thecorresponding racemates using benzylpenicillin acylase as biocatalyst(cf. J. Org. Chem. 44 2222 2225 (1979). However, a disadvantage of thisprocess is that the optical yields are very low in some cases. Inaddition, the (S)-enantiomer of the starting racemate is preferentiallyhydrolysed in this method. Thus, for example, the (R)-enantiomer ofN-p-amino-1-phenylacetyl-1-phenethylamine and the free (S)-amine areformed from the corresponding racemate. A further disadvantage is thatthe biocatalyst reacts in a very substrate-specific manner and onlythose compounds which contain a phenylacetyl group can be employed.

It is furthermore known that (S)-amines and (R)-enantiomers can beprepared from N-acylated 1-methyl-1-phenyl-alkylamines by means ofconverting racemates of N-acyl-1-methyl-1-phenyl-alkylamines usingparticular biocatalysts (cf. EP-A 0 399 589). This process suffers fromthe disadvantage that the corresponding (R)-amines can only be obtainedif the (R)-enantiomers of the N-acyl-1-methyl-1-phenyl-alkylamines aredeacylated in an additional reaction step.

It has now been found that (R)-amines of the formula ##STR3## in whichR¹ represents optionally substituted alkyl,

R² represents optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, optionally substitutedaryl or optionally substituted heterocyclyl, where, however, R¹ and R²are not identical, and

n represents the numbers 0, 1, 2 or 3,

are obtained by reacting racemic N-acylamines of the formula ##STR4## inwhich R¹, R² and n have the abovementioned meanings, and

R³ represents hydrogen, amino, dialkylamino, alkylthio, optionallysubstituted alkyl or optionally substituted alkoxy, where the carbonchain in those radicals which contain more than one carbon atom can beinterrupted by heteroatoms or heteroatom groups, or

R³ represents optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted aryl or optionally substitutedheterocyclyl,

with lipases which are suitable for cleaving the (R)-enantiomers ofN-acyl-amines of the formula (II), in the presence of water andoptionally in the presence of an organic diluent, at a pH of between 3.0and 10.0 and at temperatures of between 0° C. and 80° C.

(R)-Amines are understood to mean those optically active compounds ofthe formula (I) which exhibit the (R) configuration at theasymmetrically substituted carbon atom. In the formula (I), theasymmetrically substituted carbon atom is indicated by (*)

It is extremely surprising that (R)-amines can be prepared. by theprocess according to the invention, since the state of the art hashitherto only disclosed that (S)-amines can be obtained from racematesof N-acylamines using biocatalysts.

The process according to the invention enjoys a number of advantages.Thus, it enables (R)-amines of the formula (I) to be prepared inextremely high optical purity. It is also advantageous that theN-acylamines which are required as starting compounds are readilyaccessible and that the acyl radical can be varied over a wide range.Finally, no difficulties are involved, either, in implementing thereaction and isolating the desired substances.

In the present case, unless otherwise defined, alkyl representssaturated aliphatic hydrocarbon radicals which can be straight-chain orbranched.

In the present case, unless otherwise defined, cycloalkyl representssaturated carbocyclic radicals which optionally form a bicyclic orpolycyclic ring system with other fused or bridged rings.

In the present case, unless otherwise defined, cycloalkenyl representsunsaturated carbocyclic radicals which optionally form a bicyclic orpolycylic ring system with other fused or bridged rings.

In the present case, unless otherwise defined, aryl represents aromatic,monocyclic, bicyclic or polycyclic hydrocarbon radicals such as, forexample, phenyl, naphthyl, anthranyl or phenanthryl, preferably phenylor naphthyl, in particular phenyl.

In the present case, unless otherwise defined, heterocyclyl representssaturated or unsaturated cyclic radicals in which at least one ringmember is a heteroatom, i.e. an atom which is different from carbon. Ifthe ring contains several heteroatoms, these can then be identical ordifferent. Preferred heteroatoms are oxygen, nitrogen or sulphur. Whereappropriate, the cyclic radicals form a bicyclic or polycyclic ringsystem jointly with other carbocyclic or heterocyclic, fused or bridgedrings. Monocyclic or bicyclic ring systems are preferred, in particularmonocyclic or bicyclic ring systems having an aromatic character.

In the present case, unless otherwise defined, halogen representsfluorine, chlorine, bromine or iodine, preferably fluorine, chlorine orbromine, in particular fluorine or chlorine.

If racemic N- 1-(4-chlorophenyl)-ethyl!-acetamide is used as thestarting compound and lipase from Candida antarctica is used as thebiocatalyst, the course of the process according to the invention canthen be illustrated by the following formula scheme. ##STR5##

The racemic N-acylamines which are required as starting compounds whencarrying out the novel process are generally defined by the formula(II).

R¹ preferably represents straight-chain or branched alkyl having from 1to 8 carbon atoms, where the alkyl radicals can be substitutedidentically or differently, once or more than once, by

halogen, cyano, amino, hydroxyl, formyl, carboxyl, carbamoyl, in eachcase straight-chain or branched alkoxy or alkylthio having in each casefrom 1 to 6 carbon atoms;

in each case straight-chain or branched halogenoalkoxy orhalogenoalkylthio having in each case from 1 to 6 carbon atoms and from1 to 13 identical or different halogen atoms;

in each case straight-chain or branched alkylamino, dialkylamino,alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulphonyloxy,hydroxyiminoalkyl or alkoxyiminoalkyl having in each case from 1 to 6carbon atoms in the individual alkyl moieties;

or by doubly linked alkylene having from 1 to 6 carbon atoms or bydoubly linked dioxyalkylene having from 1 to 4 carbon atoms, where thetwo latter radicals can themselves be substituted identically ordifferently, once or more than once, by halogen, straight-chain orbranched alkyl having from 1 to 4 carbon atoms and/or straight-chain orbranched halogenoalkyl having from 1 to 4 carbon atoms and from 1 to 9identical or different halogen atoms.

R² preferably represents cycloalkyl having from 3 to 7 carbon atoms,where these radicals can be substituted identically or differently, onceto four times, by halogen and/or alkyl having from 1 to 4 carbon atoms,or

represents cycloalkenyl having from 3 to 7 carbon atoms, where theseradicals can be substituted identically or differently, once to fourtimes, by halogen and/or alkyl having from 1 to 4 carbon atoms, or

represents saturated or unsaturated, optionally benzofused, heterocyclylhaving from 3 to 7 ring members in the heterocycle, of which in eachcase from 1 to 3 are identical or different heteroatoms, such as oxygen,nitrogen or sulphur, where the radicals can be substituted identicallyor differently, once to three times, by halogen, alkyl having from 1 to4 carbon atoms, alkoxy having from 1 to 4 carbon atoms and/orhalogenoalkyl having from 1 to 4 carbon atoms and from 1 to 5 identicalor different halogen atoms, or

R² preferably represents aryl having from 6 to 10 carbon atoms, whereeach of these radicals can be substituted identically or differently,once to five times, by

halogen, cyano, nitro, amino, hydroxyl, formyl, carboxyl, carbamoyl,thiocarbamoyl;

in each case straight-chain or branched alkyl, alkoxy, alkylthio,alkylsulphinyl or alkylsulphonyl having in each case from 1 to 6 carbonatoms;

in each case straight-chain or branched alkenyl or alkenyloxy having ineach case from 2 to 6 carbon atoms;

in each case straight-chain or branched halogenoalkyl, halogenoalkoxy,halogenoalkylthio, halogenoalkylsulphinyl or halogenoalkylsulphonylhaving in each case from 1 to 6 carbon atoms and from 1 to 13 identicalor different halogen atoms;

in each case straight-chain or branched halogenoalkenyl orhalogenoalkenyloxy having in each case from 2 to 6 carbon atoms and from1 to 13 identical or different halogen atoms;

in each case straight-chain or branched alkylamino, dialkylamino,alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulphonyloxy,hydroxyiminoalkyl or alkoxyiminoalkyl having in each case from 1 to 6carbon atoms in the individual alkyl moieties;

phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy,

or by doubly linked alkylene having 3 or 4 carbon atoms or by doublylinked dioxyalkylene having 1 or 2 carbon atoms, where the two latterradicals can themselves be substituted identically or differently, onceor more than once, by halogen, straight-chain or branched alkyl havingfrom 1 to 4 carbon atoms and/or straight-chain or branched,halogenoalkyl having from 1 to 4 carbon atoms and from 1 to 9 identicalor different halogen atoms.

n also preferably represents the numbers 0, 1, 2 or 3.

R³ preferably represents hydrogen, amino, dialkylamino having from 1 to6 carbon atoms in each alkyl moiety, alkylthio having from 1 to 6 carbonatoms, straight-chain or branched alkyl having from 1 to 10 carbon atomsor straight-chain or branched alkoxy having from 1 to 6 carbon atoms,where the alkyl radicals or alkoxy radicals can be substitutedidentically or differently, once or more than once, by halogen, cyano,nitro, amino, hydroxyl, formyl, carboxyl, carbamoyl;

in each case straight-chain or branched alkoxy, alkylthio,alkylsulphinyl or alkylsulphonyl having in each case from 1 to 6 carbonatoms;

in each case straight-chain or branched alkenyl or alkenyloxy having ineach case from 2 to 6 carbon atoms;

in each case straight-chain or branched halogenoalkoxy,halogenoalkylthio, halogenoalkylsulphinyl or halogenoalkylsulphonylhaving in each case from 1 to 6 carbon atoms and from 1 to 13 identicalor different halogen atoms;

in each case straight-chain or branched alkylamino, dialkylamino,alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulphonyloxy,hydroxyiminoalkyl or alkoxyiminoalkyl having in each case from 1 to 6carbon atoms in the individual alkyl moieties;

or by doubly linked alkylene having from 1 to 6 carbon atoms or bydoubly linked dioxyalkylene having from 1 to 4 carbon atoms, where thetwo latter radicals can themselves be substituted identically ordifferently, once or more than once, by halogen, straight-chain orbranched alkyl having from 1 to 4 carbon atoms and/or straight-chain orbranched halogenoalkyl having from 1 to 4 carbon atoms and from 1 to 9identical or different halogen atoms, or

by phenyl, or

R³ preferably represents cycloalkyl having from 3 to 7 carbon atoms,where these radicals can be substituted identically or differently, onceto four times, by halogen and/or alkyl having from 1 to 4 carbon atoms,or

represents cycloalkenyl having from 3 to 7 carbon atoms, where theseradicals can be substituted identically or differently, once to fourtimes, by halogen and/or alkyl having from 1 to 4 carbon atoms, or

R³ preferably represents saturated or unsaturated heterocyclyl havingfrom 3 to 7 ring members, of which in each case from 1 to 3 areidentical or different heteroatoms, such as oxygen, nitrogen or sulphur,where the radicals can be substituted identically or differently, onceto three times, by halogen, alkyl having from 1 to 4 carbon atoms,alkoxy having from 1 to 4 carbon atoms and/or halogenoalkyl having from1 to 4 carbon atoms and from 1 to 5 identical or different halogenatoms, or

R³ preferably represents aryl having from 6 to 10 carbon atoms, whereeach of these radicals can be substituted identically or differently,once to five times, by halogen, cyano, straight-chain or branched alkylhaving from 1 to 4 carbon atoms,

straight-chain or branched halogenoalkyl having from 1 to 4 carbon atomsand from 1 to 9 identical or different halogen atoms,

straight-chain or branched alkoxy or alkylthio having from 1 to 4 carbonatoms,

straight-chain or branched halogenoalkoxy or halogenoalkylthio havingfrom 1 to 4 carbon atoms and from 1 to 9 identical or different halogenatoms,

phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy,

or by doubly linked alkylene having 3 or 4 carbon atoms or by doublylinked dioxyalkylene having 1 or 2 carbon atoms, where the two latterradicals can themselves be substituted identically or differently, onceor more than once, by halogen, straight-chain or branched alkyl havingfrom 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkylhaving from 1 to 4 carbon atoms and from 1 to 9 identical or differenthalogen atoms.

R¹ particularly preferably represents methyl, ethyl or n-propyl.

R² particularly preferably represents cyclohexyl, norbornyl orcyclohexenyl, where these radicals can be substituted identically ordifferently, once to four times, by fluorine, chlorine, methyl and/orethyl, or

represents furyl, pyridyl, thienyl, benzofuryl, quinolyl orbenzothienyl, which can be substituted identically or differently, onceto three times, by fluorine, chlorine, bromine, methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, methoxy, ethoxy,n-propoxy, i-propoxy, trifluoromethyl and/or trifluoroethyl, or

R² particularly preferably represents phenyl or naphthyl, where each ofthese radicals can be substituted identically or differently, once tofive times, by fluorine, chlorine, bromine, cyano, nitro, amino,hydroxyl, formyl, carboxyl, carbamoyl, thiocarbamoyl, methyl, ethyl, n-or i-propyl, n-, i-, s- or t-butyl, methoxy, ethoxy, n- or i-propoxy,methylthio, ethylthio, n- or i-propylthio, methylsulphinyl,ethylsulphinyl, methylsulphonyl or ethylsulphonyl, trifluoromethyl,trifluoroethyl, difluoromethoxy, trifluoromethoxy,difluorochloromethoxy, trifluoroethoxy, difluoromethylthio,difluorochloromethylthio, trifluoromethylthio, trifluoromethylsulphinylor trifluoromethylsulphonyl, methylamino, ethylamino, n- ori-propylamino, dimethylamino, diethylamino, methoxycarbonyl,ethoxycarbonyl,

phenyl, phenoxy, phenylthio, benzyloxy, benzylthio or phenylethyloxy, orby trimethylene (propane-1,3-diyl), methylenedioxy or ethylenedioxywhich are in each case doubly linked and which are in each caseoptionally substituted identically or differently, once or more thanonce, by fluorine, chlorine, methyl, trifluoromethyl, ethyl or n- ori-propyl.

n also particularly preferably represents the numbers 0, 1, 2 or 3.

R³ particularly preferably represents hydrogen, amino, dimethylamino,methylthio, methyl, ethyl, n- or i-propyl, n-, i- or s-butyl, pentyl,hexyl, heptyl, octyl, methoxy, ethoxy, methoxymethyl, hydroxymethyl,1-hydroxy-1-ethyl, 2-hydroxycarbonyl-1-hydroxy-1-ethyl,2-hydroxycarbonyl-1-ethyl, 3-hydroxy-carbonyl-1-propyl and benzyl.

The racemic N-acylamines of the formula (II) are either known or can beprepared by acylation of amines in accordance with known methods. Thus,N-acylamines of the formula (II) are obtained, for example, by reactingracemic amines with acid chlorides or acid anhydrides.

When carrying out the process according to the invention, those lipasescome into consideration as biocatalysts which are suitable forselectively cleaving the (R)-enantiomers of N-acylamines of the formula(II). Examples which may be mentioned are lipase from Candidaantarctica, Newlase F, lipase from Pseudomonas sp. and lipase M. Thelipases which can be employed as biocatalysts are known.

When carrying out the process according to the invention, the lipasescan be employed either in the native or in modified form, for examplemicroencapsulated or bound to inorganic or organic support materials.Examples of support materials which are suitable in this context arecelite, zeolites, polysaccharides, polyamides and polystyrene resins.

All the solvents which are customary for reactions of this nature comeinto consideration as organic diluents which can be employed whencarrying out the process according to the invention. Those which arepreferably utilizable are alcohols, such as methanol, ethanol,n-butanol, benzyl alcohol and phenethyl alcohol, also ethers, such astetrahydrofuran and dioxane, and, in addition, hydrocarbons, such aspentane and hexane, and, furthermore, amides, such as dimethylformamide,or else strongly polar solvents, such as dimethyl sulphoxide. Finally,emulsifiers and surface-active substances which can function asphase-transfer catalysts also come into consideration as organicdiluents. Those which preferably come into consideration are alkylarylpolyglycol ethers, polyethylene oxide fatty acid esters, polyethyleneoxide fatty alcohol ethers and ethoxylates of4-(1,1,3,3-tetramethylbutyl)-phenol.

All the customary buffering systems come into consideration foradjusting the desired pH when carrying out the process according to theinvention. Those which are preferably utilizable are sodium dihydrogenphosphate/disodium hydrogen phosphate mixtures, citrate buffers, glycinebuffers and other mixtures of suitable acids and bases.

When carrying out the process according to the invention, the pH can bevaried within a defined range. In general, the process is carried out atpH values of between 3.0 and 10.0, preferably between 4.0 and 9.0.

When carrying out the process according to the invention, the reactiontemperatures can be varied within a defined range. In general, theprocess is carried out at temperatures of between 0° C. and 80° C.,preferably between 20° C. and 70° C.

When carrying out the process according to the invention, theconcentrations of racemic N-acyl-amines of the formula (II) can bevaried within a defined range. In general, reaction mixtures are used inwhich the concentration of racemic N-acylarnine of the formula (II) isbetween 1 and 200 g/liter, preferably between 2 and 100 g/liter.

When carrying out the process according to the invention, from 0.01 to200 g, preferably from 0.05 to 100 g, of biocatalyst are generallyemployed per 1 g of racemic N-acyl-amine of the formula (II). Theworking-up is effected in accordance with customary methods. In general,the approach is to separate off the biocatalyst and to isolate thedesired components from the remaining reaction mixture by means ofdistillation, fractional crystallization, acid-base solvent extractionor by other means. When this is done, the (R)-amines of the formula (I)either result in the free state or in the form of salts from which the(R)-amines can be liberated by treating with a base. In addition, the(S)-enantiomers of the N-acylamines of the formula (II) can also beseparated from the reaction mixture. The latter enantiomers can beconverted into the free (S)-amines or their acid addition salts by anadditional chemical reaction step, for example acidic or basichydrolysis, or by enzymic means.

The (R)-amines of the formula (I) which can be prepared by the processaccording to the invention are valuable intermediates for preparingpharmaceuticals or active compounds possessing insecticidal, fungicidalor herbicidal properties (cf. EP-A 0 519 211, EP-A 0 453 137, EP-A 0 283879, EP-A 0 264 217 and EP-A 0 341 475). Thus, for example, thefungicidally active compound of the formula ##STR6## is obtained byreacting the (R)-1-(4-chloro-phenyl)-ethylamine of the formula ##STR7##with 2,2-dichloro-1-ethyl-3-methyl-1-cyclopropanecarbonyl chloride ofthe formula ##STR8## in the presence of an acid-binding agent and in thepresence of an inert organic diluent.

The implementation of the process according to the invention isillustrated by the following examples.

PREPARATION EXAMPLES Example 1 ##STR9##

A mixture of 50 mg of racemic N- 1-(4-chloro-phenyl)-ethyl!-acetamideand 100 mg of Candida antarctica lipase (Novozym 435®; E.C. no. 3.1.1.3)was made up to a volume of 10 ml using a 50 mM aqueous solution of asodium dihydrogen phosphate/disodium hydrogen phosphate buffer mixture.The reaction mixture, which had a pH of 8, was shaken at 50° C. for 168hours. After that, it was centrifuged for 5 minutes and the liquid phasewas then analysed. For this purpose, a defined volume was removed fromthe mixture and frozen at -60° C. for one hour and subsequentlyfreeze-dried. The dry sample was extracted with methanol for one hourwhile adding a molecular sieve and while treating repeatedly andvigorously with a vortex shaker. The anhydrous, methanolic phase whichwas obtained after centrifuging was analysed by gas chromatography. Aconventional reversed phase RP 18 column was used in the HPLC analysisin order to determine the concentrations of racemic amine and racemicN-acetylamine when ascertaining the conversion.

A mixture of acetonitrile/20 mM phosphate buffer, pH 2.0, 80:20 (v/v)was used as the mobile phase. A wavelength of 220 nm was employed forthe UV detection. A calibration by the external standard method wascarried out both for the racemic amine and for the N-acetyl-amine.Capillary gas chromatography was employed for the chiral analysis. Acapillary glass column having a length of 20 m was used as the column. Achiral mixed phase was used as separating material, while H₂ having acarrier gas pressure of 0.4 bar served as the carrier gas. A temperaturegradient of 80° C.//1 min iso/2.5° C./min//150° C.//10° C.//min//200° C.was employed.

The enantiomeric excess (ee-value), which is calculated as follows:##EQU1## was invoked for assessing the enantioselectivity of thereaction.

In this equation, R and S denote the concentrations of the individualenantiomers of the amine which has been formed.

In this way, it is found that the (R)-1-(4-chloro-phenyl)-ethylamine wasformed in a yield of 43% and with an ee value of >99%.

Example 2 ##STR10##

A mixture of 3 mg of racemic N- 1-(4-chloro-phenyl)ethyl!-acetamide and0.75 mg of purified free lipase B from Candida antarctica was made up toa volume of 1.5 ml using a 50 mM aqueous solution of a sodium dihydrogenphosphate/disodium hydrogen phosphate buffer mixture. The reactionmixture, which had a pH of 8, was shaken at 30° C. for 360 hours. Afterthat, it was worked up and analysed in the manner described inExample 1. By these means, it is found that the(R)-1-(4-chlorophenyl)-ethylamine was formed in a yield of 25% and withan ee value of >99%.

Example 3 ##STR11##

A mixture of 1.3 mg of racemic N- 1-(4-methylphenyl)-ethyl!-acetamideand 15 mg of Candida antarctica lipase (Novozym 435®; E.C. No. 3.1.1.3)was made up to a volume of 1.5 ml using a 50 mM aqueous solution of asodium dihydrogen phosphate/disodium hydrogen phosphate buffer mixture.The reaction mixture, which had a pH of 8, was shaken at 50° C. for 400hours. After that, it was worked up and analysed in the manner describedin Example 1. By these means, it is found that the(R)-1-(4-methylphenyl)-ethylamine was formed in a yield of 32% and withan ee value of >90%.

Example 4 ##STR12##

A mixture of 1.2 mg of racemic N-(1-phenyl-ethyl)-acetamide and 15 mg ofCandida antarctica lipase (Novozym 435®; E.C. No. 3.1.1.3) was made upto a volume of 1.5 ml using a 50 mM aqueous solution of a sodiumdihydrogen phosphate/disodium hydrogen phosphate buffer mixture. Thereaction mixture, which had a pH of 8, was shaken at 50° C. for 400hours. After that, it was worked up and analysed in the manner describedin Example 1. By these means, it is found that the(R)-1-phenyl-ethylamine was formed in a yield of 7.6% and with an eevalue of >90%.

Example 5 ##STR13##

A mixture of 200 mg (0.88 mmol) of racemic N-1-(4-chloro-phenyl)-ethyl!-methoxy-acetamide and 50 U of Candidaantarctica lipase (Novozym 435®) was made up to a volume of 7 ml using a50 mM aqueous solution of sodium dihydrogen phosphate/disodiumdihydrogen phosphate buffer mixture. The reaction mixture, which had apH value of 8, was shaken at 40° C. for 48 hours. The reaction mixturewas then extracted three times with di-isopropyl-ether. The combinedorganic phases were concentrated under reduced pressure. The remainingresidue was gas-chromatographically analysed by means of a chiralcolumn. By these means, it was found that the reaction had proceededwith a conversion rate of 48%. The (R)-1-(4-chloro-phenyl)-ethyl-amineformed showed an ee value of 99%.

An ee value of 92% was determined for the (S)-N-1-(4-chloro-phenyl)-ethyl!-methoxy-acetamide.

We claim:
 1. Process for preparing R-amines of the formula ##STR14## inwhich R¹ represents optionally substituted alkyl,R² representsoptionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted aryl oroptionally substituted heterocyclyl, where, however, R¹ and R² are notidentical, and n represents the numbers 0, 1, 2 or 3, characterized inthat racemic N-acylamines of the formula ##STR15## in which R¹, R² and nhave the abovementioned meanings, andR³ represents hydrogen, amino,dialkylamino, alkylthio, optionally substituted alkyl or optionallysubstituted alkoxy, where the carbon chain in those radicals whichcontain more than one carbon atom can be interrupted by heteroatoms orheteroatom groups, or R³ represents optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted aryl oroptionally substituted heterocyclyl, are reacted with lipases which aresuitable for cleaving the (R)-enantiomers of N-acyl-amines of theformula (II), in the presence of water and optionally in the presence ofan organic diluent, at a pH of between 3.0 and 10.0 and at temperaturesof between 0° C. and 80° C., wherein the lipases which are suitable forcleaving the (R)-enantiomers of N-acyl-amines of the formula (II) areselected from the group consisting of lipases from Candida antarctica,Newlase F. Pseudomonas sp. and lipase M.
 2. Process according to claim1, characterized in that racemic N-acylamines of the formula (II) areemployed in whichR¹² represents straight-chain or branched alkyl havingfrom 1 to 8 carbon atoms, where the alkyl radicals can be substitutedidentically or differently, once or more than once, byhalogen, cyano,amino, hydroxyl, formyl, carboxyl, carbamoyl, in each casestraight-chain or branched alkoxy or alkylthio having in each case from1 to 6 carbon atoms; in each case straight-chain or branchedhalogenoalkoxy or halogenoalkylthio having in each case from 1 to 6carbon atoms and from 1 to 13 identical or different halogen atoms; ineach case straight-chain or branched alkylamino, dialkylamino,alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulphonyloxy,hydroxyiminoalkyl or alkoxyiminoalkyl having in each case from 1 to 6carbon atoms in the individual alkyl moieties; or by doubly linkedalkylene having from 1 to 6 carbon atoms or by doubly linkeddioxyalkylene having from 1 to 4 carbon atoms, where the two latterradicals can themselves be substituted identically or differently, onceor more than once, by halogen, straight-chain or branched alkyl havingfrom 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkylhaving from 1 to 4 carbon atoms and from 1 to 9 identical or differenthalogen atoms, R² represents cycloalkyl having from 3 to 7 carbon atoms,where these radicals can be substituted identically or differently, onceto four times, by halogen and/or alkyl having from 1 to 4 carbon atoms,or R² represents cycloalkenyl having from 3 to 7 carbon atoms, wherethese radicals can be substituted identically or differently, once tofour times, by halogen and/or alkyl having from 1 to 4 carbon atoms, orR² represents saturated or unsaturated, optionally benzofusedheterocyclyl having from 3 to 7 ring members in the heterocycle, ofwhich in each case from 1 to 3 are identical or different heteroatoms,such as oxygen, nitrogen or sulphur, where the radicals can besubstituted identically or differently, once to three times, by halogen,alkyl having from 1 to 4 carbon atoms, alkoxy having from 1 to 4 carbonatoms and/or halogenoalkyl having from 1 to 4 carbon atoms and from 1 to5 identical or different halogen atoms, or R² represents aryl havingfrom 6 to 10 carbon atoms, where each of these radicals can besubstituted identically or differently, once to five times, byhalogen,cyano, nitro, amino, hydroxyl, formyl, carboxyl, carbamoyl,thiocarbamoyl; in each case straight-chain or branched alkyl, alkoxy,alkylthio, alkylsulphinyl or alkylsulphonyl having in each case from 1to 6 carbon atoms; in each case straight-chain or branched alkenyl oralkenyloxy having in each case from 2 to 6 carbon atoms; in each casestraight-chain or branched halogenoalkyl, halogenoalkoxy,halogenoalkylthio, halogenoalkylsulphinyl or halogenoalkylsulphonylhaving in each case from 1 to 6 carbon atoms and from 1 to 13 identicalor different halogen atoms; in each case straight-chain or branchedhalogenoalkenyl or halogenoalkenyloxy having in each case from 2 to 6carbon atoms and from 1 to 13 identical or different halogen atoms; ineach case straight-chain or branched alkylamino, dialkylamino,alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulphonyloxy,hydroxyiminoalkyl or alkoxyiminoalkyl having in each case from 1 to 6carbon atoms in the individual alkyl moieties; phenyl, phenoxy,phenylthio, benzyloxy, benzylthio or phenylethyloxy, or by doubly linkedalkylene having 3 or 4 carbon atoms or by doubly linked dioxyalkylenehaving 1 or 2 carbon atoms, where the two latter radicals can themselvesbe substituted identically or differently, once or more than once, byhalogen, straight-chain or branched alkyl having from 1 to 4 carbonatoms and/or straight-chain or branched halogenoalkyl having from 1 to 4carbon atoms and from 1 to 9 identical or different halogen atoms, nrepresents the numbers 0, 1, 2 or 3 and R³ represents hydrogen, amino,dialkylamino having from 1 to 6 carbon atoms in each alkyl moiety,alkylthio having from 1 to 6 carbon atoms, straight-chain or branchedalkyl having from 1 to 10 carbon atoms or straight-chain or branchedalkoxy having from 1 to 6 carbon atoms, where the alkyl radicals oralkoxy radicals can be substituted identically or differently, once ormore than once, by halogen, cyano, nitro, amino, hydroxyl, formyl,carboxyl, carbamoyl;in each case straight-chain or branched alkoxy,alkylthio, alkylsulphinyl or alkylsulphonyl having in each case from 1to 6 carbon atoms; in each case straight-chain or branched alkenyl oralkenyloxy having in each case from 2 to 6 carbon atoms; in each casestraight-chain or branched halogenoalkoxy, halogenoalkylthio,halogenoalkylsulphinyl or halogenoalkylsulphonyl having in each casefrom 1 to 6 carbon atoms and from 1 to 13 identical or different halogenatoms; in each case straight-chain or branched alkylamino, dialkylamino,alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylsulphonyloxy,hydroxyiminoalkyl or alkoxyiminoalkyl having in each case from 1 to 6carbon atoms in the individual alkyl moieties; or by doubly linkedalkylene having from 1 to 6 carbon atoms or by doubly linkeddioxyalkylene having from 1 to 4 carbon atoms, where the two latterradicals can themselves be substituted identically or differently, onceor more than once, by halogen, straight-chain or branched alkyl havingfrom 1 to 4 carbon atoms and/or straight-chain or branched halogenoalkylhaving from 1 to 4 carbon atoms and from 1 to 9 identical or differenthalogen atoms, or by phenyl, or ³ represents cycloalkyl having from 3 to7 carbon atoms, where these radicals can be substituted identically ordifferently, once to four times, by halogen and/or alkyl having from 1to 4 carbon atoms, or R³ represents cycloalkenyl having from 3 to 7carbon atoms, where these radicals can be substituted identically ordifferently, once to four times, by halogen and/or alkyl having from 1to 4 carbon atoms, or R³ represents saturated or unsaturatedheterocyclyl having from 3 to 7 ring members, of which in each case from1 to 3 are identical or different heteroatoms, such as oxygen, nitrogenor sulphur, where the radicals can be substituted identically ordifferently, once to three times, by halogen, alkyl having from 1 to 4carbon atoms, alkoxy having from 1 to 4 carbon atoms and/orhalogenoalkyl having from 1 to 4 carbon atoms and from 1 to 5 identicalor different halogen atoms, or R³ represents aryl having from 6 to 10carbon atoms, where each of these radicals can be substitutedidentically or differently, once to five times, by halogen, cyano,straight-chain or branched alkyl having from 1 to 4 carbonatoms,straight-chain or branched halogenoalkyl having from 1 to 4 carbonatoms and from 1 to 9 identical or different halogen atoms,straight-chain or branched alkoxy or alkylthio having from 1 to 4 carbonatoms, straight-chain or branched halogenoalkoxy or halogenoalkylthiohaving from 1 to 4 carbon atoms and from 1 to 9 identical or differenthalogen atoms, phenyl, phenoxy, phenylthio, benzyloxy, benzylthio orphenylethyloxy, or by doubly linked alkylene having 3 or 4 carbon atomsor by doubly linked dioxyalkylene having 1 or 2 carbon atoms, where thetwo latter radicals can themselves be substituted identically ordifferently, once or more than once, by halogen, straight-chain orbranched alkyl having from 1 to 4 carbon atoms and/or straight-chain orbranched halogenoalkyl having from 1 to 4 carbon atoms and from 1 to 9identical or different halogen atoms.
 3. Process according to claim 1,characterized in that the compound of the formula ##STR16## is employedas the racemic N-acylamine.
 4. Process according to claim 1,characterized in that it is carried out at a pH of between 4.0 and 9.0.5. Process according to claim 1, characterized in that it is carried outat temperatures of between 20° C. and 70° C.